Hexahydro-pyrido(4,3-b)indole derivatives as antipsychotic drugs

ABSTRACT

This invention concerns the compounds of formula ##STR1## the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Alk is C 1-6  alkanediyl; R 1  is hydrogen, C 1-6  alkyl, aryl or aryl C 1-6  alkyl; R 2 , R 3  and R 4  are each independently selected from hydrogen, halo, hydroxy, nitro, cyano, C 1-6  alkyl, C 1-6  alkyloxy, trifluoromethyl, C 1-6  alkylthio, mercapto, amino, mono- and di(C 1-6  alkyl)amino, carboxyl, C 1-6  alkyloxycarbonyl or C 1-6  alkylcarbonyl; R 5  is hydrogen, C 1-6  alkyl, phenyl or phenylC 1-6  alkyl; R 6  is hydrogen, C 1-6  alkyl, C 1-6  alkyloxy, C 1-6  alkylthio, or a radical of formula --NR 8  R 9 , wherein R 8  and R 9  are each independently selected from hydrogen, C 1-6  alkyl, phenyl or phenylC 1-6  alkyl; R 7  is hydrogen or C 1-6  alkyl; or R 6  and R 7  taken together may form a bivalent radical of formula --R 6  --R 7  --; having central dopamine and serotonin antogonistic activity; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. § 371of PCT/EP97/02710 filed May 15, 1997, which claims priority from EP96.201.450.2, filed May 23, 1996.

This invention relates to hexahydro-pyrido[4,3-b]indole derivativeshaving therapeutic potential in psychotic disorders, and processes fortheir preparation; it further relates to compositions comprising thesederivatives, as well as their use as a medicine.

A number of hexahydro-pyrido[4,3-b]indole compounds substituted on the2-position with an alkyl group bearing a substituted phenyl and anhydroxy, which have antipsychotic properties as evidenced by theirability to block the action of dopamine receptors of the central nervoussystem, are disclosed in J. Med. Chem. 22:677-683 (1979) and J. Med.Chem. 29:2093-2099 (1986). J. Med. Chem. 23:949-952 (1980) describes4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-fluorophenyl)-4-hydroxy-butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride as a neuroleptic agent capable of blocking dopaminereceptors.

The problem which this invention sets out to solve is to providecompounds having besides central dopamine antagonistic activity alsocentral serotonin antagonistic activity at the same dosage, acombination which is considered advantageous in potential antipsychoticdrugs.

The compounds of the present invention differ from the cited artcompounds structurally, by the fact that the tricyclichexahydro-pyrido[4,3-b]indole moiety, also known as a hexahydroγ-carboline moiety, is invariably substituted on the 2-position with analkyl group bearing a pyrimidinyl derivative, and by their favourablepharmacological properties, in particular by the fact that in additionto their excellent central dopamine antagonistic activity the compoundsof the present invention also have potent central serotonin antagonisticactivity.

The present invention concerns the compounds of formula ##STR2## theN-oxide forms, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein

Alk is C₁₋₆ alkanediyl;

R¹ is hydrogen, C₁₋₆ alkyl, aryl or arylC₁₋₆ alkyl;

R², R³ and R⁴ are each independently selected from hydrogen, halo,hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino, carboxyl,C₁₋₆ alkyloxycarbonyl and C₁₋₆ alkylcarbonyl;

R⁵ is hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₆ alkyl;

R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, or a radicalof formula --NR⁸ R⁹, wherein R⁸ and R⁹ are each independently selectedfrom hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₆ alkyl;

R⁷ is hydrogen or C₁₋₆ alkyl; or

R⁶ and R⁷ taken together may form a bivalent radical of formula --R⁶--R⁷ --,

wherein --R⁶ --R⁷ --represents

    ______________________________________                                        --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                                   (a-1),                                                  --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-2),                         --CH═CH--CH.sub.2 -- (a-3),                                               --CH.sub.2 --CH═CH-- (a-4) or                                             --CH═CH--CH═CH-- (a-5);                                             ______________________________________                                    

wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) eachindependently may be replaced by halo, C₁₋₆ alkyl, arylC₁₋₆ alkyl,trifluoromethyl, amino, hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may bereplaced by C₁₋₆ alkylidene or arylC₁₋₆ alkylidene; or

--R⁶ --R⁷ -- may also be

    ______________________________________                                        --S--CH.sub.2 --CH.sub.2 --                                                                           (a-6),                                                  --S--CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-7),                                 --S--CH═CH-- (a-8),                                                       --NH--CH.sub.2 --CH.sub.2 -- (a-9),                                           --NH--CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-10),                               --NH--CH═CH-- (a-11),                                                     --NH--CH═N-- (a-12),                                                      --S--CH═N-- (a-13) or                                                     --CH═CH--O-- (a-14);                                                    ______________________________________                                    

wherein one or where possible two or three hydrogen atoms in saidradicals (a-6) to (a-14) each independently may be replaced by C₁₋₆alkyl or aryl; and

aryl is phenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy, C₁₋₆ alkylthio, mercapto, amino, mono- and di(C₁₋₆alkyl)amino, carboxyl, C₁₋₆ alkyloxycarbonyl and C₁₋₆ alkylcarbonyl.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₆ alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl, 2,2-dimethylethyl, pentyl, hexyl, 3-methylbutyl,2-methylpentyl and the like; C₁₋₁₀ alkyl is meant to comprise C₁₋₆ alkyland the higher homologues thereof having from 7 to 10 carbon atoms suchas, for example, heptyl, octyl, nonyl, decyl and the like; C₁₋₂alkanediyl defines bivalent straight chain saturated hydrocarbonradicals having 1 or 2 carbon atoms such as, for example, methylene and1,2-ethanediyl; C₁₋₆ alkanediyl is meant to comprise C₁₋₂ alkanediyl andthe higher straight and branched chain saturated hydrocarbon homologuesthereof having from 3 to 6 carbon atoms such as, for example,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and thelike; the term C₁₋₆ alkylidene defines bivalent straight or branchchained alkylidene radicals having from 1 to 6 carbon atoms such as, forexample, methylene, ethylidene, 1-propylidene, 1-butylidene,1-pentylidene, 1-hexylidene and the like.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid andnon-toxic base addition salt forms which the compounds of formula (I)are able to form. The compounds of formula (I) which appear in theirfree form as a base can be converted in their acid addition salt bytreating said free base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methane-sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The compounds of formula (I) which appear in their free form as an acid,i.e. having at least one acidic proton, may be converted in theirpharmaceutically acceptable base addition salts by treating said freeacid form with a suitable organic or inorganic base. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium. sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term stereochemically isomeric forms as used hereinbefore definesthe possible different isomeric as well as conformational forms whichthe compounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture,and in particular the racemic mixture, of all possible stereochemicallyand conformationally isomeric forms, said mixtures containing alldiastereomers, enantiomers and/or conformers of the basic molecularstructure. All stereochemically isomeric forms of the compounds offormula (I) both in pure form or in admixture with each other areintended to be embraced within the scope of the present invention.

The numbering of the tricyclic ring-system present in the compounds offormula (I), as defined by Chemical Abstracts nomenclature is shown informula (I') ##STR3##

The compounds of formula (I) occur as "cis" or "trans" isomers. Saidterms refer to the configuration of the hydrogen atoms on carbon atoms4a and 9b of the hexahydropyrido[4,3-b]indole moiety and are inaccordance with Chemical Abstracts nomenclature. When both hydrogenatoms are on the same side of the mean plane determined by thehexahydro-pyrido[4,3-b]indole moiety then the configuration isdesignated "cis", if not, the configuration is designated "trans".

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

A special group of compounds are those compounds of formula (I) whereinone or two hydrogen atoms of the radicals (a-1) to (a-5) eachindependently are replaced by C₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy orC₁₋₁₀ alkylcarbonyloxy; and one or where possible two hydrogen atoms inthe radicals (a-6) to (a-14) each independently are replaced by C₁₋₆alkyl.

A group of interesting compounds are those compounds of formula (I)wherein R⁶ and R⁷ are taken together to form a bivalent radical offormula --R⁶ --R⁷ --, in particular a bivalent radical of formula (a-1),(a-5), (a-6) or (a-8) wherein one of the hydrogen atoms may be replacedby C₁₋₆ alkyl, in particular methyl; and R⁵ is phenyl or C₁₋₆ alkyl andpreferably is methyl.

A particular group of compounds are those compounds of formula (I)wherein Alk is C₁₋₂ alkanediyl.

Another particular group of compounds are those compounds of formula (I)wherein R¹ is hydrogen, C₁₋₆ alkyl or phenyl substituted with halo.

Still another particular group of compounds are those compounds offormula (I) wherein R² is halo or C₁₋₆ alkyloxy, in particular methoxy;and R³ and R⁴ are hydrogen.

Preferred compounds are those compounds of formula (I) wherein theconfiguration between the hydrogen atom on carbon atom 4a and thehydrogen atom on carbon atom 9b of the hexahydro-pyrido[4,3-b]indolemoiety is defined as trans.

More preferred compounds of formula (I) are those wherein R¹ ishydrogen, R² is halo and is located on the 8-position of thehexahydro-pyrido[4,3-b]indole moiety, R³ and R⁴ are both hydrogen; Alkis C₁₋₂ alkanediyl, R⁵ is phenyl or methyl; and R⁶ and R⁷ are takentogether to form a bivalent radical of formula --R⁶ --R⁷ --, inparticular a bivalent radical of formula (a-1), (a-5), (a-6) or (a-8)wherein one of the hydrogen atoms may be replaced by methyl.

Most preferred compounds of formula (I) are

3-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;and

6-[2-(8-chloro-1,3,4,4a,5,9b-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;the stereoisomeric forms and the pharmaceutically acceptable additionsalts thereof, and also the N-oxide forms thereof.

The compounds of the present invention can generally be prepared byN-alkylating an intermediate of formula (II) with an intermediate offormula (III), wherein W is an appropriate leaving group such as, forexample, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy. Thereaction can be performed in a reaction-inert solvent such as, forexample, toluene, dichloromethane, methyl isobutylketone orN,N-dimethyl-formamide, in the presence of a suitable base such as, forexample, sodium carbonate, sodium hydrogen carbonate or triethylamine,and optionally in the presence of potassium iodide. Stirring may enhancethe rate of the reaction. The reaction may conveniently be carried outat a temperature ranging between room temperature and refluxtemperature. ##STR4##

Compounds of formula (I) wherein the carbon atom of Alk by which it isattached to the nitrogen atom on the 2 position of thehexahydro-pyrido[4,3-b]indole moiety has at least one hydrogen atom,said compounds being represented by formula (I-a) and said Alk beingrepresented by Alk'H, can be prepared by reductively N-alkylating anintermediate of formula (II) with an aldehyde or ketone of formula (IV),wherein the --Alk'═O moiety is derived from an --Alk'H₂ moiety byreplacing two geminal hydrogen atoms by an oxo group, followingart-known reductive N-alkylation procedures. ##STR5##

Said reductive N-alkylation may be performed in a reaction-inert solventsuch as, for example, dichloromethane, ethanol, toluene or a mixturethereof, and in the presence of a reducing agent such as, for example, aborohydride, e.g. sodium borohydride, sodium cyanoborohydride ortriacetoxy borohydride. It may also be convenient to use hydrogen as areducing agent in combination with a suitable catalyst such as, forexample, palladium-on-charcoal or platinum-on-charcoal. In case hydrogenis used as reducing agent, it may be advantageous to add a dehydratingagent to the reaction mixture such as, for example, aluminiumtert-butoxide. In order to prevent the undesired further hydrogenationof certain functional groups in the reactants and the reaction products,it may also be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g. thiophene or quinoline-sulphur. To enhance therate of the reaction, the temperature may be elevated in a range betweenroom temperature and the reflux temperature of the reaction mixture andoptionally the pressure of the hydrogen gas may be raised.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

The intermediates of formula (II) can generally be prepared as outlinedin the following paragraphs. Some intermediates of formula (II) areart-known from J. Med. Chem. 22:677-683 (1979) and J. Med. Chem.29:2093-2099 (1986).

For instance, intermediates of formula (II) can be prepared byhydrogenation of intermediates of formula (VI), wherein R¹ is hydrogenand P is a suitable protective group such as, e.g. benzyl, andsubsequent removal of the protecting group P. For instance, when P isbenzyl, P can be removed by catalytic hydrogenation withpalladium-on-carbon in a reaction-inert solvent and in the presence ofhydrogen. ##STR6##

Said hydrogenation reaction can give intermediates of formula (V-1)wherein the configuration between the hydrogen atom on carbon atom 4aand the hydrogen atom on carbon atom 9b of thehexahydro-pyrido[4,3-b]indole moiety is defined as cis, whenintermediates of formula (VI) are submitted to art-known catalytichydrogenation procedures such as, e.g. stirring in a reaction-inertsolvent, e.g. methanol or methanolic ammonia, in the presence of asuitable catalyst, e.g. Raney nickel or palladium-on-carbon and in thepresence of hydrogen. To enhance the rate of the reaction, thetemperature may be elevated in a range between room temperature and thereflux temperature of the reaction mixture and optionally the pressureof the hydrogen gas may be raised. Intermediates of formula (V-2)wherein the configuration between the hydrogen atom on carbon atom 4aand the hydrogen atom on carbon atom 9b of thehexahydro-pyrido[4,3-b]indole moiety is defined as trans, can beprepared by treating intermediates of formula (VI) with an appropriatereagent such as, e.g. BH₃ -tetrahydro-furan complex in a reaction-inertsolvent, e.g. tetrahydrofuran, as described in J. Med. Chem. 23:949-952(1980); or NaBH₄ in a reaction-inert solvent, e.g. 2-methoxyethyl ether.

Intermediates of formula (V-a), defined as intermediates of formula (V)wherein R¹ is hydrogen, can be converted into intermediates of formula(V-b) wherein R^(1') is the same as R¹ but other than hydrogen, bysubmitting intermediates of formula (V-a) to art-known N-alkylationmethods, as described herein above. ##STR7##

A number of intermediates and starting materials are known compoundswhich may be prepared according to art-known methodologies. For example,intermediates of formula (VI) and their preparations are described in J.Med. Chem. 9:436-438 (1966), J.C.S. (C) 1235 (1968), J. Org. Chem.44:1063-1068 (1979) and J. Med. Chem. 23:635-643 (1980). Also,intermediates of formula (III) and their preparations are described inEP-A-0,037,265, EP-A-0,070,053, EP-A-0,110,435, EP-A-0,196,132 andEP-A-0,378,255.

Compounds of formula (I) and some of the intermediates in the presentinvention contain at least one asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. An alternative manner of separating the enantiomeric formsof the compounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically. The pure and mixed, inparticular racemic, stereochemically isomeric forms of the compounds offormula (I) are intended to be embraced within the scope of the presentinvention.

The compounds of formula (I) display central dopamine antagonisticactivity in combination with central serotonin antagonistic activity ascan be seen in the "apomorphine, tryptamine, norepinephrine (ATN) testin rats", described in pharmacological example C.1. Centrally actingdopamine antagonists are potential antipsychotic drugs, in particularwhen simultaneously displaying serotonin antagonism. Moreover, most ofthe compounds lack relevant α-adrenergic antagonist activity in thenorepinephrine test, suggesting absence of hypotensive activity.

The compounds of the present invention also show interestingpharmacological activity in the "mCPP Test on Rats", which test isdescribed in WO 96/14320.

The compounds of formula (I), their pharmaceutically acceptable additionsalts, stereochemically isomeric forms, or N-oxide forms thereof, areantagonists of the neurotransmitters dopamine and serotonin.Antagonizing said neurotransmitters will suppress or relieve a varietyof symptoms associated with phenomena induced by the release, inparticular the excessive release, of these neurotransmitters.Therapeutic indications for using the present compounds are mainly inthe CNS area, especially psychotic disorders such as, e.g.schizophrenia, depression, neuroses, psychoses, bipolar disorders,aggressive behaviour, anxiety, migraine and the like. Further, serotoninis a potent broncho- and vasoconstrictor and thus the presentantagonists may be used against hypertension and vascular disorders. Inaddition, serotonin antagonists have been associated with a number ofother properties such as, the suppression of appetite and promotion ofweight loss, which may prove effective in combatting obesity; and alsothe alleviation of withdrawal symptoms in addicts trying to discontinuedrinking and smoking habits. The present compounds also appear to beuseful therapeutic agents for combatting autism.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine.

In view of the usefulness of the subject compounds in the treatment orprevention of disorders associated with the release, in particular theexcessive release, of dopamine and/or serotonin, the present inventionprovides a method of treating warm-blooded animals suffering from suchdisorders, in particular psychotic disorders, said method comprising thesystemic administration of a therapeutic effective amount of a compoundof formula (I), a N-oxide or a pharmaceutically acceptable addition saltthereof, effective in treating disorders associated with the release orexcessive release of dopamine and/or serotonin in particular psychoticdisorders such as, e.g. schizophrenia, depression, neuroses, psychoses,bipolar disorders, aggressive behaviour, anxiety, migraine and the like.

For administration purposes, the subject compounds may be formulatedinto various pharmaceutical forms. To prepare the pharmaceuticalcompositions of this invention, a therapeutically effective amount ofthe particular compound, in addition salt or in free acid or base form,as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable solutions containing compounds of formula (I) maybe formulated in an oil for prolonged action. Appropriate oils for thispurpose are, for example, peanut oil, sesame oil, cottonseed oil, cornoil, soy bean oil, synthetic glycerol esters of long chain fatty acidsand mixtures of these and other oils. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wettable agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause any significant deleterious effects on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment. Addition salts of compounds offormula (I) due to their increased water solubility over thecorresponding free base or free acid form, are obviously more suitablein the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those of skill in the treatment of such disorders could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.001 mg/kg to about 1 mg/kg body weight, more preferably from about0.01 mg/kg to about 0.2 mg/kg body weight.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experimental Part

Hereinafter "THF" means tetrahydrofuran, "DIPE" means diisopropylether,"DCM" means dichloromethane, "DMF" means N,N-dimethylformamide and "ACN"means acetonitrile.

A. Preparation of the Intermediates.

EXAMPLE A.1

A mixture of ethyl1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (49.2 g),prepared as described in J. Med. Chem. 23:635-643 (1980), in NH₃ /CH₃ OH(400 ml) was hydrogenated with Raney nickel (5 g) as a catalyst. Themixture was cooled and the catalyst was filtered off. The filtrate wasevaporated. The residue was dissolved in anhydrous diethyl ether (600ml) and HCl(g) was allowed to bubble through the solution for 30minutes. The resulting precipitate was filtered off, dissolved in water(200 ml) and extracted with diethyl ether (100 ml). The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was solidified in DIPE (150 ml), cooled to 0° C., filtered offand dried, yielding 34.3 g (70%) of (±)-ethylcis-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate(intermediate 1).

EXAMPLE A.2

A mixture of intermediate 1 (22.46 g), benzoic acid (11.8 g) andthiophene (4%, 2 ml) in methanol (440 ml) was hydrogenated withpalladium-on-carbon (10%, 3 g) as a catalyst. After uptake of hydrogen(1 equivalent), the catalyst was filtered off. The filtrate wasevaporated, yielding 30 g (99%) of (±)-ethylcis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carboxylate(intermediate 2).

In a similar way, (±)-ethylcis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carboxylate(intermediate 3) and (±)-ethylcis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carboxylate(intermediate 4) were prepared.

EXAMPLE A.3

A mixture of intermediate 4 (30.2 g) and potassium hydroxide (50 g) in2-propanol (300 ml) was stirred and refluxed for 4 hours. The solventwas evaporated. Water (250 ml) was added to the residue and the organicsolvent was removed by azeotropic distillation. The aqueous residue wascooled and extracted with DCM (2×200 ml). The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas washed with petroleum ether (100 ml), filtered off and dried,yielding 15.5 g (65%) of(±)-cis-2,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-1H pyrido[4,3-b]indole(intermediate 5). In a similar way,(±)-cis-2,3,4,4a,5,9b-hexahydro-5-(2-phenylethyl)-1H-pyrido[4,3-b]-indole(intermediate6) and(±)-cis-2,3,4,4a,5,9b-hexahydro-5-methyl-1H-pyrido[4,3-b]-indole(intermediate 7) were prepared.

EXAMPLE A.4

A mixture of2,3,4,5-tetrahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[4,3-b]indolemonohydrochloride (39.5 g), prepared as described in J. Org. Chem.44:1063-1068 (1979), in 2-methoxyethyl ether (250 ml) was stirred andcooled in an ice bath, under a N₂ flow. Sodium borohydride (11.7 g,solid) was added in 8 portions. The mixture was stirred overnight atroom temperature, then cooled to 5° C. Ice water (500 ml) was addeddropwise. Precipitation resulted. The mixture was stirred for 2 hours.The precipitate was filtered off. 1,4-Dioxane (350 ml) was added and themixture was stirred. HCl (200 ml, 12N) was slowly added and the mixturewas heated to reflux temperature. The mixture was stirred and refluxedfor 1 hour, then cooled and the solvent was evaporated. The residue wasstirred in water (300 ml) and this mixture was alkalized with an aqueousNaOH solution. The mixture was stirred for 1 hour. The mixture wasextracted with DCM (2×200 ml). The combined extracts were dried,filtered and the solvent was evaporated. The residue was dissolved inDIPE (300 ml), then filtered and the filtrate was evaporated, yielding11.3 g (32%) of(±)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[4,3-b]indole(intermediate 8).

In a similar way,(±)-trans-8-chloro-2,3,4,4a,5,9b-hexahydro-2-(phenylmethyl)-1H-pyrido[4,3-b]indole(intermediate 9) was prepared.

EXAMPLE A.5

A mixture of intermediate 8 (11.3 g) in methanol (250 ml) washydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. Afteruptake of hydrogen (1 equivalent), the catalyst was filtered off and thefiltrate was evaporated. The residue was solidified in DIPE (30 ml). Theprecipitate was filtered off and dried, yielding 6.1 g (78%) of(±)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-1H-pyrido[4,3-b]indole(intermediate 10).

EXAMPLE A.6

Sodium carbonate (20.1 g) was added to a solution of intermediate 9 (45g) in DCM (500 ml). Ethyl chloroformate (20.6 g) was added dropwise at5° C. The reaction mixture was stirred for 1 hour at 5° C., then for 24hours at room temperature. More sodium carbonate (20.1 g) was added.More ethyl chloroformate (20.6 g) was added dropwise and the reactionmixture was stirred overnight at room temperature. The precipitate wasfiltered off and the filtrate was evaporated. The residue was suspendedin petroleum ether (200 ml), decanted off and the residue was dissolvedin ACN (100 ml). The compound crystallized out. The mixture was cooledto 0° C. The precipitate was filtered off and dried, yielding 26.5 g(50%) of (±)-diethyltrans-8-chloro-3,4,4a,9b-tetrahydro-2H-pyrido[4,3-b]indole-2,5(1H)-dicarboxylate(intermediate 11).

EXAMPLE A.7

Using the same reaction procedure as described in example A.3,intermediate 11 was hydrolysed to(±)-trans-8-chloro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole(intermediate 12).

EXAMPLE A.8

Borane-THF complex (1:1) (400 ml) was transferred into a 4 necked flaskwith a syringe (under N₂ flow). This solution was cooled to 0° C. Asolution of 2,3,4,5-tetra-hydro-2-(phenylmethyl)-1H-pyrido[4,3-b]indole(52.5 g), prepared as described in J. Med. Chem. 9:436-438 (1966), inTHF (400 ml) was added over a 1 hour period at 0-5° C. The reactionmixture was stirred for 1 hour at room temperature. The reaction mixturewas stirred and refluxed for 4 hours, then cooled to room temperature.6N HCl (300 ml) was added. The organic solvent was removed byevaporation. Dioxane (400 ml) was added to the residue and the mixturewas stirred and refluxed for 1 hour. The solvent was evaporated. Water(300 ml) was added to the residue and this mixture was alkalized with adiluted NaOH solution. This mixture was extracted with DCM. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CHCl₃ /CH₃ OH 95/5). The pure fractions were collected and the solventwas evaporated. The residue (20 g) was crystallized from DIPE (100 ml).The crystals were filtered off and dried, yielding 7.5 g (14%) of(±)-trans-1,3,4,4a,5,9b-hexahydro-2-(phenylmethyl)-2H-pyrido[4,3-b]indole(intermediate 13).

EXAMPLE A.9

Using the same reaction procedure as described in example A.5,intermediate 13 was converted to(±)-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (intermediate14).

B. Preparation of the Final Compounds.

EXAMPLE B.1

A mixture of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(2.45 g), disclosed in EP-0,196,132, intermediate 5 (2.7 g), sodiumcarbonate (3.3 g) and potassium iodide (0.1 g) in methyl isobutyl ketone(250 ml) was stirred and refluxed for 18 hours. The reaction mixture wascooled, filtered and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CHCl₃ /CH₃ OH90/10). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from ACN (25 ml). The crystalswere filtered off and dried, yielding 2.3 g (50%) of(±)-cis-3-[2-[1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound 9, mp. 145.1° C.).

EXAMPLE B.2

A mixture of6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.4 g),prepared as described in EP-A-0,070,053, intermediate 14 (2.6 g), sodiumcarbonate (4.8 g) and potassium iodide (0.1 g) in methyl isobutyl ketone(70 ml) was stirred for 18 hours at 90° C. The solvent was evaporated.Water (100 ml) was added and this mixture was extracted with DCM. Theseparated organic layer was dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CHCl₃ /CH₃ OH 95/5). The pure fractions werecollected and the solvent was evaporated. The residue was treated withACN (15 ml). The solid was filtered off and dried, yielding 1.5 g (28%)of(±)-trans-6-[2-(1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(compound 11, mp. 152.5° C.).

EXAMPLE B.3

Using the same reaction procedure as described in example B.1,6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.4 g),prepared as described in EP-A-0,070,053, was reacted with(±)-trans-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,prepared as described in J. Med. Chem. 22:677--(1979), to form(±)-trans-6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(compound 15, mp. 140.9° C.).

EXAMPLE B.4

A mixture of6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrobromide (3.6 g), prepared as described in EP-0,110,435,(±)-trans-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole(2.9 g), described in J. Med. Chem. 29:2093--(1986), and sodiumcarbonate (3.2 g) in DMF (70 ml) was stirred for 18 hours at 90° C. Thecooled reaction mixture was poured out into water (400 ml) and theresulting precipitate was filtered off and dissolved in DCM (200 ml).This organic solution was washed with water (50 ml), dried, filtered andthe solvent was evaporated. The residue was solidified in DIPE (50 ml),filtered off and dissolved in methanol (300 ml). The solution wastreated for 30 minutes with activated charcoal. This mixture wasfiltered over dicalite. The filtrate was evaporated. The residue waswashed in methanol (20 ml). The precipitate was filtered off, dried andpurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 98/2). The pure fractions were collected and the solvent wasevaporated. The residue was washed with methanol (5 ml) and dried,yielding: 1.5 g (31%) of(±)-trans-6-[2-[8-fluoro-5-(4-fluoro-phenyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(compound 22, mp. 110° C.).

Tables 1 and 2 list the compounds that were prepared according to one ofthe above Examples.

                                      TABLE 1                                     __________________________________________________________________________      #STR8##                                                                       Co.  No. Ex.  No. R.sup.2 R.sup.1                                                                                     --R.sup.6 --R.sup.7 -- Physical                                             data  (mp. in ° C.)            __________________________________________________________________________     1 B.2                                                                              H    H          cis   --S--CH═CH--                                                                          mp. 165.4° C.                     2 B.4   H     H      cis  --S--CH═C(CH.sub.3)--     mp. 149.6.degre                                            e.  C.                                   3 B.2   H     H      cis  --CH═CH--CH═CH--     mp. 109.6.degree                                            . C.                                     4 B.2   H   --CH.sub.3     cis    --S--CH═CH-- .HCl.2(H.sub.2 O)/                                                                     mp.                                                    167.4° C.                         5 B.1   H   --CH.sub.3     cis  --CH═CH--CH═CH-- .3HCl.3/2H.sub                                            .2 O                                               mp. 194° C.                                                  6 B.4   H   --CH.sub.3     cis      --(CH.sub.2).sub.4 -- .2HCl.1/2(H.s                                            ub.2 O)                                                                         mp. 210.4 °C.                   7 B.1   H --CH.sub.2 C.sub.6 H.sub.5   cis    --S--CH═CH--                                                     mp. 132.8° C.                     8 B.1  H --CH.sub.2 C.sub.6 H.sub.5   cis    --S--CH.sub.2 --CH.sub.2                                              --      .1/2(H.sub.2 O)                                                                   mp. 126.1° C.                                                9 B.1   H --CH.sub.2 C.sub.6                                                H.sub.5   cis  --CH═CH--CH.dbd                                            .CH--     mp. 145.1° C.                                                 10 B.1   H --(CH.sub.2).sub.2                                                C.sub.6 H.sub.5 cis  --CH═CH--                                            CH═CH--      mp. 108°                                              C.                                      11 B.2   H     H      trans  --S--CH═CH--       mp. 152.5°                                               C.                                      12 B.4   H     H      trans  --S--CH═C(CH.sub.3)--   mp. 215.7.degre                                            e. C.                                   13 B.4   H     H      trans  --S--CH.sub.2 --CH.sub.2 --      mp.                                                   99.1° C.                         14 B.2   H     H      trans --CH═CH--CH═CH--     mp. 172.8.degre                                            e. C.                                   15 B.3    F    H      trans  --S--CH═CH--        mp. 140.9°                                              C.                                      16 B.1    F    H      trans  --S--CH═C(CH.sub.3)--    mp. 83.2.degre                                            e. C.                                   17 B.2    F    H      trans --CH═CH--CH═CH--      mp. 193.7.degr                                            ee. C.                                  18 B.1    F    H      trans    --(CH.sub.2).sub.4 --       mp. 203.5.deg                                            ree. C.                                 19 B.2    H    --CH.sub.3   trans  --S--CH═CH--     .(E)-butenedioat                                            e mp.                                                                    205.0° C.                             20  B.2 H    --CH.sub.3   trans  --CH═CH--CH═CH--     .2HCl.H.su                                            b.2 O                                                                                           mp. 240°                                             C.                                      21  B.2 H    --CH.sub.3   trans     --(CH.sub.2).sub.4 --    .2HCl mp.                                              >260° C.                          - 22  B.2 F                                                                                                                   trans    --S--CH═CH                                            --      mp. 197.2° C.                                                    - 23  B.3 F                                                                            trans    --S--CH.sub.2                                             --CH.sub.2 --     mp. 110°                                             C.                                       - 24  B.4 F                                                                                                                   trans  --S--CH═C(CH                                            .sub.3)--    mp. 184.7° C.        - 25  B.2 F                                                                                                                   trans     --(CH.sub.2).                                            sub.4 --      mp. 145.5°                                               C.                                       - 26  B.1 Cl    H     trans    --S--CH═CH--      mp. 224.9°                                             C.                                      27  B.1 Cl    H     trans  --S--CH═C(CH.sub.3)--    mp. 201.3.degree                                            . C.                                    28  B.1 Cl    H     trans  --CH═CH--CH═CH--    mp. 192.6°                                             C.                                     29  B.1 --OCH.sub.3  H     trans    --S--CH═CH--      mp. 201.4.degr                                            ee. C.                                  30  B.1 --OCH.sub.3  H     trans  --CH═CH--CH═CH--    mp.                                                   166.8° C.                      __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________      #STR14##                                                                    Co.                                                                              Ex.                            Phys. data                                    No. No.   R.sup.2    R.sup.1   R.sup.5      R.sup.6       R.sup.7                                             (mp. in ° C.)                        __________________________________________________________________________    31 B.1                                                                              F H          --CH.sub.3                                                                        --NHCH.sub.2 C.sub.6 H.sub.5                                                         --CH.sub.3                                                                        mp. 96.8° C.                            - 32  B.2   F                                                                                                        --CH.sub.3 --NHCH.sub.2 C.sub.6                                       H.sub.5   --CH.sub.3  mp. 217.2°                                       C.                                             -                                                                          33 B.2                                                                              H --CH.sub.3 --C.sub.6 H.sub.5                                                                 --CH═CH--CH═CH--*                                                                 .2HCl.H.sub.2 O mp.                                                                                     198.2°                                        C.                                        __________________________________________________________________________     *: R.sup.6 and R.sup.7 taken together to form a bivalent radical of           formula --R.sup.6 --R.sup.7 ---                                          

C. Pharmacological Example

EXAMPLE C.1 "Apomorphine, Tryptamine, Norepinephrine (ATN) Test in Rats"

The central dopamine antagonistic and serotonin antagonistic activity ofthe subject compounds is evidenced by the experimental data obtained inthe combined apomorphine (APO), tryptamine (TRY) and norepinephrine(NOR) test in rats. Said combined apomorphine, tryptamine andnorepinephrine test is described in Arch. Int. Pharmacodyn., 227,238-253 (1977) and provides an empirical evaluation of the relativespecificity with which drugs may effect particular neurotransmittersystems centrally (CNS) as well as peripherally. In this test, rats wereobserved for effects or responses indicating peripheral and centralactivity. Central dopamine antagonism is evaluated by challenging rats,subcutaneously pretreated with different doses of the test compound,with apomorphine which is a dopamine agonist. Next, serotonin antagonismis evaluated by challenging the same rats, subcutaneously pretreatedwith different doses of the test compound, with tryptamine which is anagonist at serotonin 5HT₂ -receptors. Both central and peripheralserotonin antagonism can be assessed in this test. Centrally actingserotonin antagonists are potential antipsychotic drugs, in particularwhen simultaneously displaying dopamine antagonism in the first part ofthis test. Finally, α-adrenergic antagonistic activity of the testcompounds is evaluated by challenging the same rats, subcutaneouslypretreated with different doses of the test compound, withnorepinephrine which is an α-adrenergic agonist.

The experimental data are summarized in Table 3 and expressed as ED₅₀values in mg/kg body weight, which are defined as the dose at which eachof the tested compounds protects 50% of the tested animals from arelevant response evoked by the above-mentioned challenging substances.Column APO lists the results of the apomorphine challenge, indicatingcentral dopamine antagonistic activity. Column TRY convulsions and TRYhyperaemia list the results of the tryptamine challenge, indicatingcentral and peripheral serotonin antagonistic activity respectively.Column NOR lists the results of the norepinephrine challenge, indicatingα-adrenergic antagonist activity. The favourable pharmacologicalproperties of the compounds of formula (I) lie in their potent centraldopamine (column APO) and serotonin (column TRY convulsions)antagonistic activity.

                  TABLE 3                                                         ______________________________________                                                 Combined test in rats, ED.sub.50  in mg/kg                           Compound          TRY         TRY                                               Number APO convulsions hyperaemia NOR                                       ______________________________________                                        11         0.31   0.31        ≦0.04                                                                          >10                                       12 1.25 1.25 0.02 >10                                                         13 2.5 5 ≦0.04 >10                                                     14 0.31 1.25 ≦0.16 >10                                                 15 0.31 0.31 ≦0.0025 >10                                               16 0.25 0.45 0.015 >10                                                        17 0.08 0.5 ≦0.04 ≧10                                           18 0.31 2 0.02 >10                                                            19 8 1.25 0.31 5                                                              20 1.25 1.25 ≦0.63 5                                                   22 1.25 1.25 0.08 0.5                                                         23 0.12 0.08 ≦0.01 0.03                                                24 5 1.25 ≦0.04 0.31                                                   25 0.31 0.12 0.02 0.08                                                        26 0.03 0.02 0.005 >10                                                        27 0.31 0.31 0.005 >10                                                        28 0.08 0.12 0.005 >10                                                        29 5 5 0.02 ≧10                                                        30 ≧10 2 ≦0.16 >10                                              31 1.25 ≧10 ≦0.16 >10                                         ______________________________________                                    

D. Composition Examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable addition saltor a stereochemically isomeric form thereof.

EXAMPLE D.1 Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I.

EXAMPLE D.2 Film-Coated Tablets Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture is sieved, dried and sieved again. Then there are added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole is mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

EXAMPLE D.3 Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE D.4 Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

We claim:
 1. A compound of formula (I) ##STR16## a N-oxide form, apharmaceutically acceptable addition salt or a stereochemically isomericform thereof, whereinAlk is C₁₋₆ alkanediyl; R¹ is hydrogen, C₁₋₆ alkyl,aryl or arylC₁₋₆ alkyl; R², R³ and R⁴ are each independently selectedfrom hydrogen, halo, hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy, C₁₋₆ alkylthio, mercapto, amino, mono- and di(C₁₋₆alkyl)amino, carboxyl, C₁₋₆ alkyloxycarbonyl or C₁₋₆ alkylcarbonyl; R⁵is hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₆ alkyl; R⁶ is hydrogen,C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, or a radical of formula-NR⁸R⁹, wherein R⁸ and R⁹ are each independently selected from hydrogen,C₁₋₆ alkyl, phenyl or phenylC₁₋₆ alkyl; R⁷ is hydrogen or C₁₋₆ alkyl; orR⁶ and R⁷ taken together may form a bivalent radical --R⁶ --R⁷ --,wherein --R⁶ --R⁷ --represents ##STR17## wherein one or two hydrogenatoms of said radicals (a-1) to (a-5) each independently may be replacedby halo, C₁₋₆ alkyl, arylC₁₋₆ alkyl, trifluoromethyl, amino, hydroxy,C₁₋₆ alkyloxy or C₁₋₁₀ alkylcarbonyloxy; or where possible, two geminalhydrogen atoms may be replaced by C₁₋₆ alkylidene or arylC₁₋₆alkylidene; or --R⁶ --R⁷ --may also be ##STR18## wherein one or wherepossible two or three hydrogen atoms in said radicals (a-6) to (a-14)each independently may be replaced by C₁₋₆ alkyl or aryl; and aryl isphenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, nitro, cyano, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy, C₁₋₆ alkylthio, mercapto, amino, mono- and di(C₁₋₆alkyl)amino, carboxyl, C₁₋₆ alkyloxycarbonyl and C₁₋₆ alkylcarbonyl. 2.A compound according to claim 1 wherein one or two hydrogen atoms of theradicals (a-1) to (a-5) each independently are replaced by C₁₋₆ alkyl,C₁₋₆ alkyloxy, hydroxy or C₁₋₁₀ alkylcarbonyloxy; and one or wherepossible two hydrogen atoms in the radicals (a-6) to (a-14) eachindependently are replaced by C₁₋₆ alkyl.
 3. A compound according toclaim 1 wherein the configuration between the hydrogen atom on carbonatom 4a and the hydrogen atom on carbon atom 9b of thehexahydro-pyrido[4,3-b]indole moiety is defined as trans.
 4. A compoundaccording to claim 1 wherein R⁶ and R⁷ are taken together to form abivalent radical of formula (a1), (a-5), (a-6) or (a-8) wherein one ofthe hydrogen atoms may be replaced by C₁₋₆ alkyl; and R⁵ is phenyl orC₁₋₆ alkyl.
 5. A compound according to claim 1 wherein R¹ is hydrogen,R² is halo, R³ and R⁴ are both hydrogen; Alk is C₁₋₂ alkanediyl, R⁵ isphenyl or C₁₋₆ alkyl; and R⁶ and R⁷ are taken together to form abivalent radical of formula (a-1), (a-5), (a-6) or (a-8) wherein one ofthe hydrogen atoms may be replaced by C₁₋₆ alkyl.
 6. A compoundaccording to claim 1 wherein the compound is3-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;or6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;or6-[2-(8-chloro-1,3,4,4a,5,9b-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;the stereoisomeric forms and the pharmaceutically acceptable additionsalts thereof, or an N-oxide form thereof.
 7. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound asclaimed in claim
 1. 8. A process of preparing a pharmaceuticalcomposition comprising intimately mixing a therapeutically effectiveamount of a compound as claimed in claim 1 with a pharmaceuticallyacceptable carrier.
 9. A method of treating a warm-blooded animalsuffering from a psychotic disorder comprising administering to thewarm-blooded animal a therapeutically effective amount of the compoundof claim
 1. 10. The method of claim 9, wherein the pyschotic disorder isschizophrenia.